U.S. patent number 6,930,110 [Application Number 10/491,151] was granted by the patent office on 2005-08-16 for substituted alkylaminopyridazinone derivatives, process for the preparation thereof and pharmaceutical composition containing the same.
This patent grant is currently assigned to Egis Gyogyszergyar Rt.. Invention is credited to Jozsef Barkoczy, Andras Egyed, Istvan Gacsalyi, Laszlo Harsing, Hajnalka Kompagne, Aniko Miklosne Kovacs, Gyorgy Levay, Csilla Leveleki, Bernadett Martonne Marko, Peter Kotay Nagy, Eva Schmidt, Gyula Simig, Gabor Szenasi, Janos Wellmann.
United States Patent |
6,930,110 |
Barkoczy , et al. |
August 16, 2005 |
Substituted alkylaminopyridazinone derivatives, process for the
preparation thereof and pharmaceutical composition containing the
same
Abstract
The invention relates to substituted alkylaminopyridazinone
derivatives of the general Formula (I), (wherein R.sub.1 is
hydrogen or alkyl having 1-4 carbon atoms; one of X and Y stands
for hydrogen or halogen and the other represents a group of the
general Formula (II), R.sub.2 is hydrogen or alkyl having 1-4
carbon atoms; n is 1, 2 or 3; R.sub.3 stands for hydrogen, alkyl
having 1-4 carbon atoms or aryl-(C.sub.1-4 alkyl); Z stands for
oxygen; or R.sub.3 and Z together with the groups placed between
them form a piperazine ring; and R.sub.4 stands for hydrogen,
halogen, trifluoromethyl or alkoxy having 1-4 carbon atoms) and
pharmaceutically acceptable acid addition salts thereof. The
invention compounds are useful in the treatment of anxiolytic
conditions and cognitive disorders.
Inventors: |
Barkoczy; Jozsef (Budapest,
HU), Egyed; Andras (Budapest, HU),
Gacsalyi; Istvan (Budapest, HU), Harsing; Laszlo
(Budapest, HU), Kompagne; Hajnalka (Budapest,
HU), Nagy; Peter Kotay (Vac, HU), Levay;
Gyorgy (Budakeszi, HU), Leveleki; Csilla
(Budapest, HU), Marko; Bernadett Martonne (Budapest,
HU), Kovacs; Aniko Miklosne (Budapest, HU),
Schmidt; Eva (Budapest, HU), Simig; Gyula
(Budapest, HU), Szenasi; Gabor (Budapest,
HU), Wellmann; Janos (Budapest, HU) |
Assignee: |
Egis Gyogyszergyar Rt.
(Budapest, HU)
|
Family
ID: |
10975085 |
Appl.
No.: |
10/491,151 |
Filed: |
June 28, 2004 |
PCT
Filed: |
September 26, 2002 |
PCT No.: |
PCT/HU02/00096 |
371(c)(1),(2),(4) Date: |
June 28, 2004 |
PCT
Pub. No.: |
WO03/02709 |
PCT
Pub. Date: |
April 03, 2003 |
Foreign Application Priority Data
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|
|
|
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Sep 27, 2001 [HU] |
|
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0103912 |
|
Current U.S.
Class: |
514/252.01;
544/238 |
Current CPC
Class: |
C07D
405/12 (20130101); C07D 237/22 (20130101); C07D
403/12 (20130101); A61P 25/00 (20180101); C07D
401/12 (20130101); A61P 25/14 (20180101); A61P
25/22 (20180101); A61P 25/24 (20180101); A61P
25/28 (20180101) |
Current International
Class: |
C07D
401/00 (20060101); C07D 403/00 (20060101); C07D
403/12 (20060101); C07D 237/22 (20060101); C07D
401/12 (20060101); C07D 237/00 (20060101); C07D
405/12 (20060101); C07D 405/00 (20060101); A61K
031/501 (); C07D 405/14 (); C07D 405/12 () |
Field of
Search: |
;544/238
;514/252.01 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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0 372 305 |
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Jun 1990 |
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EP |
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164 079 |
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Jun 1994 |
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PL |
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WO 96 38441 |
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Dec 1996 |
|
WO |
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WO 99 64402 |
|
Dec 1996 |
|
WO |
|
Primary Examiner: Dentz; Bernard
Attorney, Agent or Firm: Birch, Stewart, Kolasch &
Birch, LLP
Parent Case Text
This application is a 371 of PCT/HU02/00096 filed Sep. 26, 2002.
Claims
What we claim is:
1. Compounds of Formula ##STR11##
wherein R.sub.1 is hydrogen or alkyl having 1-4 carbon atoms; one
of X and Y stands for hydrogen or halogen and the other represents
a group of Formula ##STR12## R.sub.2 is hydrogen or alkyl having
1-4 carbon atoms; n is 1, 2 or 3; R.sub.3 stands for hydrogen,
alkyl having 1-4 carbon atoms or aryl-(C.sub.1-4 alkyl); Z stands
for oxygen; or R.sub.3 and Z together with the groups placed
between them form a piperazine ring; and R.sub.4 stands for
hydrogen, halogen, trifluoromethyl or alkoxy having 1-4 carbon
atoms,
and pharmaceutically acceptable acid addition salts thereof.
2. Compounds of Formula I according to claim 1, wherein R.sub.1 is
hydrogen or methyl; one of X and Y stands for hydrogen or chlorine
and the other represents a group of Formula II; R.sub.2 is hydrogen
or methyl; n is 1, 2 or 3; R.sub.3 stands for hydrogen; Z stands
for oxygen; or R.sub.3 and Z together with the groups placed
between them form a piperazine ring; and R.sub.4 stands for
hydrogen or chlorine,
and pharmaceutically acceptable acid addition salts thereof.
3.
5-chloro-4-{4-[4-(2,3-dihydrobenzo[1,4]dioxine-5-yl)-piperazine-1-yl]-buty
lamino}-2H-piridazin-3-one and pharmaceutically acceptable acid
addition salts thereof.
4.
4-chloro-5-{2-[4-(2,3-dihydro-1,4-benzodioxine-5-yl)-piperazin-1-yl]-ethyl
amino}-2-methyl-2H-piridazin-3-one and pharmaceutically acceptable
acid addition salts thereof.
5.
4-chloro-5-{2-[4-(2,3-dihydrobenzo[1,4]dioxine-5-yl)-piperazin-1-yl]ethyl}
methylamino-2H-pyridazin-3-one and pharmaceutically acceptable acid
addition salts thereof.
6.
4-{3-[2-(2,3-dihydrobenzo[1,4]dioxine-5-yloxy)ethylamino]-propylamino}-2H-
pyridazine-3-one and pharmaceutically acceptable acid addition
salts thereof.
7.
5-{2-[4-(2,3-dihydro-1,4-benzodioxine-5-yl)-piperazine-1-yl]-ethylamino}-2
H-pyridazine-3-one and pharmaceutically acceptable acid addition
salts thereof.
8.
5-{2-[4-(7-chloro-2,3-dihydrobenzo[1,4]dioxine-5-yl)-piperazine-1-yl]ethyl
amino}-2H-pyridazine-3-one and pharmaceutically acceptable acid
addition salts thereof.
9.
5-{3-[4-(2,3-dihydro-1,4-benzodioxine-5-yl)piperazine-1-yl]-propylamino}-2
H-pyridazine-3-one and pharmaceutically acceptable acid addition
salts thereof.
10.
5-{2-[2-(2,3-dihydrobenzo[1,4]dioxine-5-yloxy)ethylamino)-ethylamino)-2H-p
yridazine-3-one and pharmaceutically acceptable acid addition salts
thereof.
11.
5-{2-[4-(2,3-dihydro1,4-benzodioxine-5-yl)-piperazine-1-yl]-ethylamino}-2-
methyl-2H-pyridazine-3-one and pharmaceutically acceptable acid
addition salts thereof.
12.
5-({2-[4-(2,3-dihydro-benzo[1,4]dioxine-5-yl)-piperazine-1-yl]-ethyl}-meth
yl-amino)-2H-pyridazine-3-one and pharmaceutically acceptable acid
addition salts thereof.
13.
5-(2-(4-(2,3-dihydro-benzo[1,4]dioxine-5-yl)-piperazine-1-yl)-ethyl-methyl
-amino)-2-methyl-2H-pyridazin-3-one and pharmaceutically acceptable
acid addition salts thereof.
14.
4-chloro-5-({2-[4-(2,3-dihydro-benzo[1,4]dioxine-5-yl)-piperazine-1-yl]-et
hyl}-methyl-amino)-2-methyl-2H-pyridazine-3-one and
pharmaceutically acceptable acid addition salts thereof.
15.
5-{2-[2-(2,3-dihydro-benzo[1,4]dioxine-5-yl-oxy)-ethyl-amino]-ethyl-amino}
-2-methyl-2H-pyridazine-3-one and pharmaceutically acceptable acid
addition salts thereof.
16. Process for the preparation of compounds of Formula I
wherein R.sub.1 is hydrogen or alkyl having 1-4 carbon atoms; one
of X and Y stands for hydrogen or halogen and the other represents
a group of Formula II; R.sub.2 is hydrogen or alkyl having 1-4
carbon atoms; n is 1, 2 or 3; R.sub.3 stands for hydrogen, alkyl
having 1-4 carbon atoms or aryl-(C.sub.1-4 alkyl); Z stands for
oxygen; or R.sub.3 and Z together with the groups placed between
them form a piperazine ring; and R.sub.4 stands for hydrogen,
halogen, trifluoromethyl or alkoxy having 1-4 carbon atoms,
and pharmaceutically acceptable acid addition salts thereof, which
comprises: a) for the preparation of compounds of Formula I,
wherein X represents hydrogen or halogen, Y stands for a group of
Formula II and R.sub.2, R.sub.3, R.sub.4, Z and n are as stated
above, reacting a compound of Formula ##STR13## wherein L.sub.1
represents a leaving group, and R.sub.1, R.sub.2, X and n are as
stated above, with an amine of Formula ##STR14## wherein R.sub.3,
R.sub.4 and Z are as stated above; or b) for the preparation of
compounds of Formula I, wherein Y represents hydrogen or halogen, X
stands for a group of Formula II and R.sub.2, R.sub.3, R.sub.4, Z
and n are as stated above, reacting a compound of Formula ##STR15##
wherein L.sub.2 is a leaving group, and R.sub.1, R.sub.2, Y and n
are as stated above, with an amine of Formula IV wherein R.sub.3,
R.sub.4 and Z are as stated above; or c) for the preparation of
compounds of Formula I, wherein X represents hydrogen or halogen, Y
stands for a group of Formula II and R.sub.2, R.sub.3, R.sub.4, Z
and n are as stated above, with the proviso that R.sub.3 together
with Z and the groups between them is other than a piperazine ring,
reacting a compound of Formula ##STR16## VI, wherein R.sub.1,
R.sub.2, R.sub.3, X and n are as stated above, with a compound of
Formula ##STR17## wherein R.sub.4 and Z are as stated above and
L.sub.3 stands for a leaving group; or d) for the preparation of
compounds of Formula I, wherein Y stands for hydrogen or halogen, X
stands for a group of Formula II and R.sub.2, R.sub.3, R.sub.4, Z
and n are as stated above with the proviso that R.sub.3 together
with Z and the groups between them is other than a piperazine ring,
reacting a compound of Formula ##STR18## wherein R.sub.1, R.sub.2,
R.sub.3, Y and n are as stated above, with a compound of Formula
VII, wherein Z and R.sub.4 are as stated above and L.sub.3 stands
for a leaving group; or e) for the preparation of compounds of
Formula I, wherein X represents halogen and Y stands for a group of
Formula II and/or Y represents halogen and X stands for a group of
Formula II and R.sub.1, R.sub.2, R.sub.3, R.sub.4, Z and n are as
stated above, reacting a dihalopyridazinone derivative of Formula
##STR19## wherein R.sub.1 is as stated above and X and Y
independently from each other stand for halogen, with a compound of
Formula ##STR20## wherein R.sub.2, R.sub.3, R.sub.4, Z and n are as
stated above, and, if desired, subjecting an obtained substituted
alkylaminopyridazinone derivative of Formula I, wherein X or Y
stand for halogen, to catalytic dehalogenation to obtain a
substituted alkylaminopyridazinone derivative of Formula I or its
hydrochloride salt, wherein X represents hydrogen and Y stands for
a group of Formula II or X represents a group of Formula II and Y
stands for hydrogen; and/or converting a compound of Formula I into
a pharmaceutically acceptable acid addition salt thereof or
liberating a compound of Formula I from an acid addition salt
thereof.
17. Pharmaceutical compositions comprising as active ingredient at
least one compound of Formula I according to claim 1 or
pharmaceutically acceptable acid addition salts thereof in
admixture with suitable inert pharmaceutical carriers and/or
auxiliary agents.
18. Pharmaceutical compositions according to claim 17 comprising as
active ingredient
5-chloro-4-{4-[4-(2,3-dihydrobenzo[1,4]dioxine-5-yl)-piperazine-1-yl]-butyl
amino}-2H-piridazin-3-one;
4-chloro-5-{2-[4-(2,3-dihydro-1,4-benzodioxine-5-yl)-piperazine-1-yl]-ethyl
amino}-2-methyl-2H-piridazin-3-one;
4-chloro-5-{2-[4-(2,3-dihydrobenzo[1,4]dioxine-5-yl)-piperazine-1-yl]ethyl}
methylamino-2H-pyridazin-3-one;
4-{3-[2-(2,3-dihydrobenzo[1,4]dioxine-5-yloxy)ethylamino]-propylamino}-2H-p
yridazine-3-one;
5-{2-[4-(2,3-dihydro-1,4-benzodioxine-5-yl)-piperazine-1-yl]-ethylamino}-2H
-pyridazine-3-one;
5-{2-[4-(7-chloro-2,3-dihydrobenzo[1,4]dioxine-5-yl)-piperazine-1-yl]ethyla
mino}-2H-pyridazine-3-one;
5-{3-[4-(2,3-dihydro-1,4-benzodioxine-5-yl)piperazine-1-yl]-propylamino}-2H
-pyridazine-3-one;
5-{2-[2-(2,3-dihydrobenzo[1,4]dioxine-5-yloxy)ethylamino)-ethylamino)-2H-py
ridazine-3-one;
5-{2-[4-(2,3-dihydro1,4-benzodioxine-5-yl)-piperazine-1-yl]-ethylamino}-2-m
ethyl-2H-pyridazine-3-one;
5-(-{2-[4-(2,3-dihydro-benzo[1,4]-benzodioxine-5-yl)-piperazine-1-yl]-ethyl
}-methyl-amino)-2H-pyridazine-3-one;
5-(2-(4-(2,3-dihydro-benzo[1,4]dioxine-5-yl)-piperazine-1-yl)-ethyl-methyl-
amino)-2-methyl-2H-pyridazine-3-one;
4-chloro-5-({2-[4-(2,3-dihydro-benzo[1,4]dioxine-5-yl)-piperazine-1-yl]-eth
yl}-methyl-amino)-2-methyl-2H-pyridazine-3-one;
5-{2-[2-(2,3-dihydro-benzo[1,4]dioxine-5-yl-oxy)-ethyl-amino]-ethyl-amino}-
2-methyl-2H-pyridazine-3-one;
and pharmaceutically acceptable acid addition salts thereof.
19. Process for the preparation of pharmaceutical compositions
according to claim 17 which comprises admixing at least one
compound of Formula I or a pharmaceutically acceptable acid
addition salt thereof with suitable inert pharmaceutical carriers
and/or auxiliary agents.
20. Method of treatment of anxiolytic conditions and cognitive
disorders which comprises administering to a person in need of such
treatment a pharmaceutically effective amount of a compound of
Formula I according to claim 1 or a pharmaceutically acceptable
acid addition salt thereof.
Description
FIELD OF THE INVENTION
The invention relates to new substituted alkylaminopyridazinone
derivatives, process for the preparation thereof and pharmaceutical
compositions containing the same.
BACKGROUND OF THE INVENTION
The present invention relates to the use of compounds of general
Formula I for the treatment of different forms of anxiety.
Anxiety is a major CNS symptom accompanied by many psychiatric
disorders, medical and surgical conditions and stress situations.
Benzodiazepines such as diazepam, chlordiazepoxide, and alprazolam
etc. are the most commonly used agents in the various anxiety
disorders. However, sedative and amnestic side effects are a major
disadvantage of these drugs especially in disorders affecting
active, working populations. Moreover, withdrawal symptoms may
occur following suspension of benzodiazepine administration after
long term therapy. Therefore, finding of an effective
anxiolytic/antistress compound without such undesirable side
effects, low addictive potential and good safety features still
remains one of the most challenging aims of CNS pharmacology
research these days.
Piperazinylalkylamino-3(2H)-pyridazinone derivatives having blood
pressure lowering effect and being suitable for the treatment of
heart failure and peripheral circulatory disturbances are known
from EP-A No. 372 305.
SUMMARY OF THE INVENTION
The object of the present invention is to provide new anxiolytic
active ingredients free of antihypertensive properties.
The above object is achieved by the present invention.
The present invention is directed to new compounds of the general
Formula ##STR1##
(wherein R.sub.1 is hydrogen or alkyl having 1-4 carbon atoms; one
of X and Y stands for hydrogen or halogen and the other represents
a group of the general Formula ##STR2## R.sub.2 is hydrogen or all
having 1-4 carbon atoms; n is 1, 2 or 3; R.sub.3 stands for
hydrogen, alkyl having 1-4 carbon atoms or aryl-(C.sub.1-4 alkyl);
Z stands for oxygen; or R.sub.3 and Z together with the groups
placed between them form a piperazine ring; and R.sub.4 stands for
hydrogen, halogen, trifluoromethyl or alkoxy having 1-4 carbon
atoms)
and pharmaceutically acceptable acid addition salts thereof.
According to a further feature of the present invention there is
provided a process for the preparation of compounds of the general
Formula I
(wherein R.sub.1 is hydrogen or alkyl having 1-4 carbon atoms; one
of X and Y stands for hydrogen or halogen and the other represents
a group of the general Formula II; R.sub.2 is hydrogen or alkyl
having 1-4 carbon atoms; n is 1, 2 or 3; R.sub.3 stands for
hydrogen, alkyl having 1-4 carbon atoms or aryl-(C.sub.1-4 alkyl);
Z stands for oxygen; or R.sub.3 and Z together with the groups
placed between them form a piperazine ring; and R.sub.4 stands for
hydrogen, halogen, trifluoromethyl or alkoxy having 1-4 carbon
atoms)
and pharmaceutically acceptable acid addition salts thereof which
comprises a) for the preparation of compounds of the general
Formula I, (wherein X represents hydrogen or halogen, Y stands for
a group of the general Formula II and R.sub.2, R.sub.3, R.sub.4, Z
and n are as stated above) reacting a compound of the general
Formula ##STR3## (wherein L.sub.1 represents a leaving group, and
R.sub.1, R.sub.2, X and n are as stated above) with an amine of the
general Formula ##STR4## (wherein R.sub.3, R.sub.4 and Z are as
stated above); or b) for the preparation of compounds of the
general Formula I, (wherein Y represents hydrogen or halogen, X
stands for a group of the general Formula II and R.sub.2, R.sub.3,
R.sub.4, Z and n are as stated above), reacting a compound of the
general Formula ##STR5## (wherein L.sub.2 is a leaving group, and
R.sub.1, R.sub.2, Y and n are as stated above) with an amine of the
general Formula IV (wherein R.sub.3, R.sub.4 and Z are as stated
above); or c) for the preparation of compounds of the general
Formula I, (wherein X represents hydrogen or halogen, Y stands for
a group of the general Formula II and R.sub.2, R.sub.3, R.sub.4, Z
and n are as stated above, with the proviso that R.sub.3 together
with Z and the groups between them is other than a piperazine
ring), reacting a compound of the general Formula ##STR6## (wherein
R.sub.1, R.sub.2, R.sub.3, X and n are as stated above) with a
compound of the general Formula ##STR7## (wherein R.sub.4 and Z are
as stated above and L.sub.3 stands for a leaving group); or d) for
the preparation of compounds of the general Formula I, (wherein Y
stands for hydrogen or halogen, X stands for a group of the general
Formula II and R.sub.2, R.sub.3, R.sub.4, Z and n are as stated
above with the proviso that R.sub.3 together with Z and the groups
between them is other than a piperazine ring), reacting a compound
of the general Formula ##STR8## (wherein R.sub.1, R.sub.2, R.sub.3,
Y and n are as stated above) with a compound of the general Formula
VII (wherein Z and R.sub.4 are as stated above and L.sub.3 stands
for a leaving group); or e) for the preparation of compounds of the
general Formula I, (wherein X represents halogen and Y stands for a
group of the general Formula II and/or Y represents halogen and X
stands for a group of the general Formula II and R.sub.1, R.sub.2,
R.sub.3, R.sub.4, Z and n are as stated above), reacting a
dihalopyridazinone derivative of the general Formula ##STR9##
(wherein R.sub.1 is as stated above and X and Y independently from
each other stand for halogen) with a compound of the general
Formula ##STR10## (wherein R.sub.2, R.sub.3, R.sub.4, Z and n are
as stated above), and, if desired, subjecting an obtained
substituted alkylaminopyridazinone derivative of the general
Formula I (wherein X or Y stand for halogen) to catalytic
dehalogenation to obtain a substituted alkylaminopyridazinone
derivative of the general Formula I or its hydrochloride salt,
wherein X represents hydrogen and Y stands for a group of the
general Formula II or X represents a group of the general Formula
II and Y stands for hydrogen; and/or converting an obtained
compound of the general Formula I into a pharmaceutically
acceptable acid addition salt thereof or liberating a compound of
the general Formula I from an acid addition salt thereof.
According to a still further feature of the present invention there
are provided pharmaceutical compositions comprising as active
ingredient at least one compound of the general Formula I or a
pharmaceutically acceptable acid addition salt thereof in admixture
with suitable inert pharmaceutical carriers and/or auxiliary
agents.
According to a still further feature of the present invention there
is provided a process for the preparation of pharmaceutical
compositions which comprises admixing at least one compound of the
general Formula I or a pharmaceutically acceptable acid addition
salt thereof with suitable inert pharmaceutical carriers and/or
auxiliary agents.
According to a still further feature of the present invention there
is provided the use of compounds of the general Formula I or
pharmaceutically acceptable acid addition salts thereof as
pharmaceutical active ingredients.
According to a still further feature of the present invention there
is provided a method of treatment of anxiolytic conditions and
cognitive disorders which comprises administering to the person in
need of such treatment a pharmaceutically effective amount of a
compound of the general Formula I or a pharmaceutically acceptable
acid addition salt thereof.
DESCRIPTION OF THE PREFERRED EMBODIMENT
The definition of the term used in the description and the claims
is as follows:
The term "halogen" is fluorine, chlorine, bromine and iodine,
preferably chlorine.
The term "alkyl having 1-4 carbon atoms" relates to straight or
branched chain alkyl groups, preferably methyl, ethyl, isopropyl,
n-propyl, n-butyl, sec.-butyl, isobutyl or tert.-butyl.
The term "alkoxy having 1-4 carbon atoms" relates to straight or
branched chain alkoxy groups, preferably methoxy, ethoxy,
isopropoxy or n-butoxy, preferably methoxy.
The term "aryl-(C.sub.1-4 alkyl)" is e.g. benzyl,
.beta.-phenyl-ethyl etc., preferably benzyl.
The term "leaving group" relates to halogen (e.g. chlorine,
bromine) or alkylsulfonyloxy groups (e.g. methylsulfonyloxy) or
arylsulfonyloxy groups (e.g. benzylsulfonyloxy,
p-toluene-sulfonyloxy).
The term "pharmaceutically acceptable acid addition salts of the
substituted alkylaminopyridazinone derivatives of the Formula I"
relates to the non-toxic acid addition salts of the compounds
formed with inorganic acids such as hydrochloric acid, hydrobromic
acid, sulfuric acid, phosphoric acid etc. or organic acids such as
formic acid, acetic acid, maleic acid, fumaric acid, lactic acid,
tartaric acid, succinic acid, citric acid, benzenesulfonic acid,
p-toluenesulfonic acid, methanesulfonic acid etc.
The following compounds form a preferred sub-group of the invention
compounds, namely compounds of the general Formula I
(wherein R.sub.1 is hydrogen or methyl; one of X and Y stands for
hydrogen or chlorine and the other represents a group of the
general Formula II; R.sub.2 is hydrogen or methyl; n is 1, 2 or 3;
R.sub.3 stands for hydrogen; Z stands for oxygen; or R.sub.3 and Z
together with the groups placed between them form a piperazine
ring; and R.sub.4 stands for hydrogen or chlorine)
and pharmaceutically acceptable acid addition salts thereof.
The following compounds of the general Formula I and
pharmaceutically acceptable acid addition salts possess
particularly useful pharmaceutical properties:
5-chloro-4-{4-[4-(2,3-dihydrobenzo[1,4]dioxine-5-yl)-piperazine-1-yl]-butyl
amino}-2H-piridazine-3-one;
4-chloro-5-{2-[4-(2,3-dihydro-1,4-benzodioxine-5-yl)-piperazine-1-yl]-ethyl
amino}-2-methyl-2H-piridazine-3-one and its monohydrate;
4-chloro-5-{2-[4-(2,3-dihydrobenzo[1,4]dioxine-5-yl)-piperazine-1-yl]ethyl}
methylamino-2H-pyridazine-3-one;
4-{3-[2-(2,3-dihydrobenzo[1,4]dioxine-5-yloxy)ethylamino]-propylamino}-2H-p
yridazine-3-one;
5-{2-[4-(2,3-dihydro-1,4-benzodioxine-5-yl)-piperazine-1-yl]-ethylamino}-2H
-pyridazine-3-one;
5-{2-[4-(7-chloro-2,3-dihydrobenzo[1,4]dioxine-5-yl)-piperazine-1-yl]ethyla
mino}-2H-pyridazine-3-one;
5-{3-[4-(2,3-dihydro-1,4-benzodioxine-5-yl)piperazine-1-yl]-propylamino}-2H
-pyridazine-3-one;
5-{2-[2-(2,3-dihydrobenzo[1,4]dioxine-5-yloxy)ethylamino)-ethylamino)-2H-py
ridazine-3-one;
5-{2-[4-(2,3-dihydro1,4-benzodioxine-5-yl)-piperazine-1-yl]-ethylamino}-2-m
ethyl-2H-pyridazine-3-one;
5-({2-[4-(2,3-dihydro-benzo[1,4]dioxine-5-yl)-piperazine-1-yl]-ethyl}-methy
l-amino)-2H-pyridazine-3-one;
5-(2-(4-(2,3-dihydro-benzo[1,4]dioxine-5-yl)-piperazine-1-yl)-ethyl-methyl-
amino)-2-methyl-2H-pyridazine-3-one;
4-chloro-5-({2-[4-(2,3-dihydro-benzo[1,4]dioxine-5-yl)-piperazine-1-yl]-eth
yl}-methyl-amino)-2-methyl-2H-pyridazine-3-one;
5-{2-[2-(2,3-dihydro-benzo[1,4]dioxine-5-yl-oxy)-ethyl-amino]-ethyl-amino}-
2-methyl-2H-pyridazine-3-one.
In case of processes (a), (b), (c), (d) and (e) of the invention,
the reactions are carried out in a manner similar to the known
analogous processes, see e.g. March, J.: Advanced Organic
Chemistry, Reactions, Mechanism and Structure, 4.sup.th Edition,
John Wiley and Sons, New York, 1992.
In process (e) of the invention, usually, a mixture of the
compounds of the general Formula I is formed, that is a mixture of
the compound, wherein X represents a group of the Formula II and Y
stands for halogen, and the one, wherein X represents halogen and Y
stands for a group of the general Formula II, depending on the
starting substances used. The components of the mixture are
separated by conventional methods of the preparative organic
chemistry e.g. fractionated crystallization.
When a substituted alkylaminopyridazinone derivative of the Formula
I, wherein X or Y stands for halogen, preferably chlorine, is
subjected to catalytic hydrogenation, then dehalogenation proceeds
and the corresponding substituted alkylaminopyridazinone derivative
of the general Formula I or its hydrochloride salt, wherein X or Y
stands for hydrogen, is formed.
The catalytic hydrogenation is carried out in an analogous manner
as the processes described in the literature [e.g. March, J.:
Advanced Organic Chemistry, Reactions, Mechanism and Structure
4.sup.th Edition, John Wiley and Sons, New York, 1992]. As the
hydrogen source, for example, hydrogen gas, hydrazine, hydrazine
hydrate, formic acid, a trialkylammonium formate or an alkali metal
formate can be used. The catalyst is suitably palladium, platinum
oxide, Raney nickel etc. The reaction can be performed in the
presence or absence of an acid binding agent. As acid binding
agent, an inorganic base such as sodium hydroxide or an organic
base such as hydrazine, triethyl amine, diisopropyl ethyl amine
etc. can be used. The reaction can be carried out in an indifferent
protic or aprotic solvent or a mixture thereof. The protic solvent
is, for example, an alkanol, water or mixtures thereof, the aprotic
solvent is suitably dioxane, tetrahydrofurane or dichloro methane.
In general, the reaction temperature is 0-150.degree. C.,
preferably 20-100.degree. C.
The preparation of the acid addition salt from the free base of the
Formula I and the liberation of the base from the acid addition
salt are carried out in a manner known per se.
The alkylaminopyridazinone derivatives of the Formulae III and V
used as the starting compounds can be prepared by the process
described in the International Patent Application No.
PCT/HU98/00054 (WO 99/64402).
The amines of the Formula IV are partly known compounds. The novel
ones can be prepared in an analogous way [Pollard et al., J. Am.
Chem. Soc., 56, 2199 (1934)].
A part of the aminoalkylaminopyridazinone derivatives of the
Formulae VI and VIII is also known from the literature. The novel
compounds can be prepared in an analogous manner as described in
the literature [Haerer et al., Arzneim. Forsch., 39(6), 714-716
(1989)].
The compounds of the Formula VII are partly known, too. The novel
compounds can be prepared by employing the methods described in the
literature [Augstein, J. et al., J. Med. Chem., 8, 356-367
(1965)].
The dihalopyridazinone derivatives of the Formula IX are partly
known. The novel compounds can be prepared by using the methods
known from the literature [Homer et al., J. Chem. Soc., 1948,
2194].
The compounds of the Formula X can be prepared from the
corresponding amine of the Formula IV in a manner known per se
[Shigenaga, S. et al., Arch. Pharm., 329(1), 3-10 (1996); Janssens,
F. et al., J. Med. Chem., 28(12), 1934-1943 (1985); He Xiao Shu et
al., Bioorg. Med. Chem. Lett., 7(18), 2399-2402 (1997)].
The pharmacological effect of the substituted
alkylaminopyridazinone derivatives of the general Formula I was
studied on the following tests.
Anxiolytic Effect
Vogel Lick-conflict
Experiments were performed in a PC operated system (LIIKOSYS,
Experimentria, Hungary) consisted of 8 test chambers (20
cm.times.20 cm.times.20 cm Plexiglas boxes) each of which was
equipped with a water fountain system mounted at appropriate height
on the wall of the chamber and metal grid floor for delivering
electric shocks. 160-180 g male Wistar rats N=8) were deprived of
drinking water 48 h and fasted for 24 h prior to test. Test and
reference compounds or vehicle were administered intraperitoneally,
30 min prior to test. All procedures were carried out in a quiet,
air-conditioned room between 07:30 and 13:00 h at an ambient
temperature of 23.+-.2.degree. C. At the beginning of the test the
animals were placed in the test chamber where they had free access
to drinking water for a 30 s grace period. After that, electric
shocks (600 .mu.A, 0.6 s) were applied through the drinking spout
following every 20 licks during the 5 min test period (Vogel et al,
1971). Number of punished licks were recorded and stored by an IBM
compatible computer. Means.+-.SEM of numbers of tolerated shocks
were calculated in each group, statistical analysis of data was
performed by one way ANOVA followed by Duncan's test (STATISTICA).
The results obtained are shown in Table 1. Diazepam
[7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepine-2-one]
was used as the reference substance.
TABLE 1 Vogel's drinking conflict test Compound (Example No.) MED
in mg/kg ip. 2 20.0 4 20.0 6 <5.0 7 <10.0 10 5.0 11 20.0
Diazepam 5.0
The data of table 1 indicate that the substituted
alkylaminopyridazinone derivatives of the Formula I have
significant anxiolytic effect equivalent to that of diazepam.
Elevated Plus-maze Test in Rats
Tests have been performed as described by Pellow and co-workers [J.
Neurosci. Methods, 14, 149 (1985)]. A wooden cross, 15 cm wide with
100 cm long arms was used for the experiments. The sides and ends
of two opposite arms of the cross were equipped with 40 cm high
walls, however, the arms were open to the 15.times.15 cm central
area (closed arms). The two other opposite arms were not encircled
by walls (open arms).
Male Sprague-Dawley rats weighing 200-220 g were used for the
experiments. The animals were placed in the central area of the
equipment 60 min after treatment and the following four parameters
have been observed for the 5 min test time:
time spent in the open arms,
time spent in the closed arms,
number of entries into the open arms,
number of entries into the closed arms.
The effect was expressed as percent increase in either the time
(measured in sec) spent in the open arms or number of entries into
the open arms. MEDs (minimal effective dose) were determined for
each compound regarding the time spent in the open arms. The
results obtained are summarized in Table 2. Buspirone
[8-{4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl}-8-azaspiro[4,5]decane-7,9-di
one] was used as the reference substance.
TABLE 2 Elevated plus-maze test in rats Compound (Example No.) MED
in mg/kg po. 2 10.0 3 10.0 4 1.0 5 0.003 9 0.3 10 0.01 Buspirone
3.0
From Table 2 it is evident that the substituted
alkylaminopyridazinone derivatives of the Formula I have
outstanding anxiolytic activity in the above test, considerably
exceeding the efficacy of the reference substance.
Sedative Effect
Inhibition of Spontaneous Motor Activity
The effect on spontaneous motor activity was investigated according
to Borsy and co-workers [Borsy, J. et al, Arch. Int. Pharmacodyn.,
124, 180-190 (1960)] in a ten channel Dews instrument, with 1-1
animal in each channel. Animals were placed into the instrument 60
min after per os treatment with either vehicle or test compound,
and interruptions of infrared beams were recorded for 30 min. From
these data, 50 per cent. Inhibitory doses (ID.sub.50)have been
determined by regression analysis. The results obtained are shown
in Table 3. Diazepam was used as the reference substance.
TABLE 3 Inhibition of spontaneous motility in mouse Compound
(Example No.) ID.sub.50 in mg/kg po. 4 30.0 5 11.0 9 >30.0 10
53.3 Diazepam 7.0
In contrast to the diazepam used as the reference substance, the
tested substituted alkylaminopyridazinone derivatives of the
Formula I display sedative effect only in a relatively high
dose.
Effects on Blood Pressure
The experiments were performed in conscious, freely moving, male
Wistar rats using a radiotelemetry system (Data Sciences
International, St. Paul, Minn., USA). Prior to treatments rats were
implanted with transmitters (type: TL11M2-C50-PXT) that permitted
continues monitoring of arterial blood pressure. Under sterile
surgical conditions, catheter of the transmitter was introduced
into the abdominal aorta for measurement of arterial blood pressure
and the transmitter was sutured to the abdominal wall of animals
anaesthetised with pentobarbital-Na (60 mg/kg, i.p.; Nembutal inj.
Phylaxia-Sanofi, Budapest). After surgery the animals were treated
with an antibiotic (1 ml/kg i.m. Tardomyocel comp. inj. ad us.
vet., Bayer A G, Leverkusen, Germany). A 7 day postoperative
recovery period was allowed. Radio signals emitted by the
transmitters were detected by RLA1000 type receivers placed under
each animal's cage. The data were collected, saved and evaluated
using the Dataquest IV. software from Data Sciences. The computer
was set to sample the parameters for 10 seconds in every second
minute.
The test substances or vehicle (methyl cellulose 0.4% w/v) were
administered orally by gavage in a volume of 1 ml/kg at about 10
a.m. The effects of test items were measured for 6 hours. The
effect of each compound was compared with that caused by vehicle
treatment using two-way analysis of variance for repeated measures
with Scheffe's post hoc test.
Data obtained are shown in the Table 4. None of the compounds
examined reduced blood pressure of the test animals.
TABLE 4 Effects of different test compounds or vehicle on mean
arterial blood pressure for 6 hours after treatment in conscious
rats Mean blood pressure after treatment after treatment with test
with placebo compound Results of (mmHg) (mmHg) statistical Example
Mean S.E. Mean S.E. evaluation 8 91.5 2.9 95.4 2.2 N.S. 7 96.0 2.7
97.0 2.1 N.S. 6 101.5 3.8 106.3 2.7 N.S. 12 91.5 2.9 89.9 2.5 N.S.
11 91.5 2.9 101.5 3.9 N.S. 16 99.1 1.9 105.2 1.6 N.S. S.E. =
Standard Error (of the mean); N.S. = Not significant statistically
(when compared to placebo)
According to data presented here the compounds of present invention
have no effect on blood pressure, indicating the lack of
antihypertensive potential.
Effect of Cognition and Memory
Male Wistar rats weighing 200-220 g were used. The animals were
obtained from Charles River Co. They were kept in a room with
normal 12-12 h light-dark cycle (light on: 06:00) at relative
humidity of 60.+-.10%.
The experiment was performed in a five-channel "step through"-type
passive avoidance learning apparatus. The equipment consisted of
two adjacent Plexi-glass boxes of 20.times.20.times.16 cm. One of
them was made of regular transparent Plexi-glass and the other one
was made of black, non-transparent Plexi-glass. The boxes were
connected with a 7.5.times.8 cm passage way, equipped with a
computer-controlled guillotine-door. The passage of the rats
through the door was detected by infrared photocells arranged in
two parallel lines in the opening of the passage way. The door was
automatically closed when the animals passed through. The dark
compartment was equipped with stainless steel grid floor through
which electric foot shocks could have been delivered to the
animals. A 10 W light bulb was installed above the passage way in
the light compartment.
The experiment was performed on two consecutive days, in two
sessions which were 24 h apart from each other.
On Day 1 (Acquisition) the animals acquired information about the
situation (grid floor shock in the dark compartment), on Day 2
(Retention) they recalled the acquired information to avoid
punishment ("if I go into the dark I will be punished, so I stay
outside in the light").
Day 1 (Acquisition)
The individually numbered animals were placed into the light
compartment of the equipment. After 30 s the guillotine door was
opened and the rats could freely pass to the dark (considered as
safe) compartment. Step through latency was automatically
determined. (Step-trough latency is the time period spanning from
door opening to the time when the animal passed into the dark
compartment.) The door was closed then, and the timer was
automatically stopped. An electric foot shock of 1.2 mA lasting 2.5
s was applied to the animal through the grid floor 3 s after the
door has been closed, except for rats in the absolute control group
(no shock+vehicle treated). Test animals were removed from the dark
compartment immediately after foot shock has been delivered. The
function of the absolute control group was to show that shocked
animals will remember the unpleasant foot shock as revealed by
increased latency time when compared to absolute control. That is
the essence of acquisition.
Day 2 (Retention)
After 24 h, the animals were placed again in the light compartment
of the test apparatus and step-through latency was measured as
described at Acquisition day, except that no foot shock was applied
to the animals in any group on the second day. A maximum of 180 s
time interval was available for the rats to pass into the dark
compartment. The animals were removed from the light compartment if
they did not pass to the dark compartment within the 180 s test
period.
The investigators surprisingly found that the invention compounds
significantly increased step-through latency into the dark
compartment of the passive avoidance apparatus after Day 2
administration of the compound (FIG. 1).
It is shown on FIG. 1 that in absolute control group(no shock,
untreated), step-trough latency was approximately the same on both
experimental days (meaning that there was nothing to recall and
avoid on the second day).
In the shocked, vehicle-treated control group the unavoidable 1.2
mA foot shock resulted in a significantly increased step-through
latency on Day 2 when compared to absolute control. The
experimental animals recalled the annoying experience (foot shock)
in the dark, therefore, they pass into the dark compartment with a
significantly longer time (increased latency).
In the treated groups this augmented latency has been further
increased after the Day 2 treatment indicating that the retention
of memory has been improved.
These surprising effects are not evident since anxiolytic compounds
(i.e. diazepam) have a deleterious effect on memory.
From therapeutic point of view the advantageous effect of compounds
of general Formula I on learning and memory signifies that the
compounds could be appropriate for treating and/or preventing
diseases or conditions accompanying diseases wherein learning or
memory functions are suffering a loss or there is a possibility to
suffering a loss. Such diseases are, but not limited to--as
mentioned earlier--Alzheimer's disease, Korsakoff syndrome,
Huntington's disease, Parkinson's disease and mental decline due to
ageing processes, impairment of the cognitive functions or to
exposure to toxic substances as well.
Based on the above test data, the substituted
alkylaminopyridazinone derivatives of the general Formula I are
effective in the treatment of various clinical patterns connected
with anxiety. In case of certain compounds, the anxiolytic
potential exceeds by several orders of magnitude the effect of the
marketed reference substances (diazepam, buspirone). Sedative
side-effect appears only in a dose that is multiple of the one
needed to produce the expected therapeutical effect. This means
that the substituted alkylaminopyridazinone derivatives of the
general Formula I do not have sedative, life quality deteriorating
side-effects which are characteristic of benzodiazepines.
Summarized, the compounds of general Formula I surprisingly in an
unforeseen manner possess considerable anxiolytic properties
without sedative side effects in their anxiolytic dose range. In
addition to the the anxiolytic efficacy, the compounds of general
Formula I have advantageous effects on cognition and memory.
According to our studies the compounds of general Formula I
surprisingly have no antihypertensive potential.
Based on the above tests, the compounds of the invention and
pharmaceutically suitable acid addition salts thereof can be used
as active ingredients in pharmaceutical compositions.
Furthermore, the invention refers to a pharmaceutical composition
comprising a substituted alkylaminopyridazinone derivative of
general Formula I or a pharmaceutically suitable acid addition salt
thereof and one or more conventional carriers.
The pharmaceutical composition of the invention contains, in
general, 0.1 to 95 per cent by weight, preferably 1 to 50 per cent
by weight, suitably 5 to 30 per cent by weight of the active
ingredient.
The pharmaceutical composition of the invention is suitable for
peroral, parenteral, rectal or transdermal administration or for
local treatment, and can be solid or liquid.
The solid pharmaceutical compositions suitable for peroral
administration may be powders, capsules, tablets, film-coated
tablets, microcapsules etc., and can comprise binding agents such
as gelatine, sorbitol, poly(vinyl-pyrrolidone) etc.; filling agents
such as lactose, glucose, starch, calcium phosphate etc.; auxiliary
substances for tabletting such as magnesium stearate, talc,
poly(ethylene glycol), silica etc.; wetting agents such as sodium
laurylsulfate etc. as the carrier.
The liquid pharmaceutical compositions suitable for peroral
administration may be solutions, suspensions or emulsions and can
comprise e.g. suspending agents such as gelatine,
carboxymethylcellulose etc.; emulsifiers such as sorbitane
monooleate etc.; solvents such as water, oils, glycerol, propylene
glycol, ethanol etc.; preservatives such as methyl
p-hydroxybenzoate etc. as the carrier.
Pharmaceutical compositions suitable for parenteral administration
consist of sterile solutions of the active ingredient, in
general.
Dosage forms listed above as well as other dosage forms are known
per se, see e.g. Remington's Pharmaceutical Sciences, 18.sup.th
Edition, Mack Publishing Co., Easton, USA (1990).
The pharmaceutical composition contains dosage unit, in general. A
typical dose for adult patients amounts to 0.1 to 1000 mg of the
compound of the Formula I or a pharmaceutically suitable acid
addition salt thereof calculated for 1 kg body weight, daily. The
daily dose can be administered in one or more portions. The actual
dosage depends on many factors and is determined by the
physician.
The pharmaceutical composition is prepared by admixing a compound
of the Formula I or a pharmaceutically suitable acid addition salt
thereof to one or more carrier(s), and converting the mixture
obtained to a pharmaceutical composition in a manner known per se.
Useful methods are known from the literature, e.g. Remington's
Pharmaceutical Sciences mentioned above.
The pharmaceutical composition containing a substituted
alkylaminopyridazinone derivative of the Formula I or a
pharmaceutically suitable acid addition salt thereof is prepared in
a similar way as the pharmaceutical composition containing the
novel substituted alkylaminopyridazinone derivative of the Formula
I or a pharmaceutically suitable acid addition salt thereof as the
active ingredient.
Further details of the present invention are to be found in the
following Examples without limiting the scope of protection to said
Examples.
EXAMPLES
Example 1
Preparation of
5-chloro-4-(3-((2-(2,3-dihydrobenzo[1,4]dioxine-5-yloxy)-ethyl)methyl-amin
o)-propyl-amino)-2H-pyridazine-3-one oxalate
A mixture of 2.66 g (0.01 moles) of
4-(3-bromopropylamino)-5-chloro-2H-pyridazine-3-one, 2.51 g (0.012
moles) of 2-(2,3-dihydrobenzo[1,4]dioxine-5-yloxy)ethylmethylamine,
2.8 cm.sup.3 (0.02 moles) of triethylamine and 40 cm.sup.3 of
acetone is stirred at reflux temperature under reflux for 120
hours. Then, the reaction mixture is cooled, filtered, and the
mother liquor is evaporated under reduced pressure. The residue
obtained is subjected to chromatography over a silica gel column
using a 1:1:2 mixture of acetone, ethyl acetate and chloroform as
the eluent. The fractions containing the active substance are
collected, evaporated, and the residue is dissolved in a 15:1
mixture of diethyl ether and ethyl acetate. To the solution
obtained, a solution of oxalic acid in diethyl ether is added, drop
by drop, at room temperature under stirring. The crystals obtained
are filtered and washed with diethyl ether.
Thus, 2.76 g (57.0%) of the title compound are obtained. M.p.:
115-117.degree. C.
Analysis: for C.sub.20 H.sub.25 ClN.sub.4 O.sub.8 (484.90); calc.:
C, 49.54%; H, 5.20%; Cl, 7.31%; N, 11.55%; found: C, 49.04%; H,
5.11%; Cl, 7.18%; N, 11.42%.
IR (KBr): 3300, 1720, 1640, 1610, 1114.
.sup.1 H-NMR (DMSO-d.sub.6, i400): 12.8 (b, 1H), 7.60 (s, 1H), 6.77
(bt, J=6.7 Hz, 1H), 6.74 (.about.t, J=8.2 Hz, 1H), 6.60 (dd, J1=1.5
Hz, J2=8.3 Hz, 1H), 6.53 (dd, J1=1.4 Hz, J2=8.2 Hz, 1H), 4.27 (t,
J=5.1 Hz, 2H), 4.22 (s, 4H), 3.69 (.about.q, J=6.7 Hz, 2H), 3.38
(t, J=5.0 Hz, 2H), 3.10 (.about.t, J=7.7 Hz, 2H), 2.78 (s, 3H),
1.95 (m, 2H).
Example 2
Preparation of
5-chloro-4-(3-{[2-(2,3-dihydrobenzo[1,4]dioxine-5-yloxy)-ethyl]propyl-amin
o}propylamino)-2H-pyridazine-3-one
A mixture of 1.33 g (0.005 moles) of
4-(3-bromopropylamino)-5-chloro-2H-pyridazine-3-one, 1.42 g (0.006
moles) of
(2-(2,3-dihydrobenzo[1,4]dioxine-5-yloxy)ethyl)propylamine, 1.01 g
(0.01 moles) of triethylamine and 20 cm.sup.3 of acetone is stirred
under reflux at reflux temperature for 32 hours. Then, the reaction
mixture is cooled, filtered, and the mother liquor is evaporated
under reduced pressure. The residue obtained is subjected to
chromatography over a silica gel column using a 1:1 mixture of
acetone and ethyl acetate. The fractions containing the active
substance are collected, evaporated, and suspended in diisopropyl
ether. The crystals obtained are filtered, and washed with diethyl
ether.
Thus, 1.52 g (72.0%) of the title compound are obtained. M.p.:
87-89.degree. C.
Analysis: for C.sub.20 H.sub.27 ClN.sub.4 O.sub.4 (422.92); calc.:
C, 56.80%; H, 6.44%; Cl, 8.38%; N, 13.25%; found: C, 56.48%; H,
6.62%; Cl, 8.17%; N, 13.01%;
IR (KBr): 3328, 1642, 1612.
.sup.1 H-NMR (CDCl.sub.3, g200): 11.05 (b, 1H), 7.49 (s, 1H), 6.71
(m, 1H), 6.49 (m, 2H), 6.60 (bt, J=6.6 Hz, 1H), 4.27 (m, 4H), 4.12
(t, J=6.4 Hz, 2H), 3.87 (.about.q, J=6.4 Hz, 2H), 2.93 (t, J=6.4
Hz, 2H), 2.69 (t, J=6.2 Hz, 2H), 2.51 (.about.t, J=7.6 Hz, 2H),
1.80 (.about.qn, J=6.4 Hz, 2H), 1.54 (.about.bx, J=7.5 Hz, 2H),
0.89 ((t, J=7.3 Hz, 3H).
.sup.13 C-NMR (CDCl.sub.3, g200): 157.77, 148.22, 144.26, 140.86,
140.19, 133.51, 120.05, 110.00, 106.77, 105.41, 67.50, 64.38,
64.17, 57.13, 53.01, 52.87, 43.40, 28.12, 20.19, 11.80.
Example 3
Preparation of
4-{3-[benzyl-[2-(2,3-dihydrobenzo[1,4]dioxine-5-yloxy)ethyl]-amino]propyla
mino}-5-chloro-2H-pyridazine-3-one hydrochloride
A mixture of 5.3 g (0.02 moles) of
4-(3-bromopropylamino)-5-chloro-2H-pyridazine-3-one, 7.82 g (0.027
moles) of
benzyl-[2-(2,3-dihydro-benzo[1,4]dioxine-5-yloxy)ethyl]amine, 5.6
cm.sup.3 (0.04 moles) of triethylamine and 150 cm.sup.3 of acetone,
is stirred at reflux temperature under reflux for 24 hours. Then,
the reaction mixture is evaporated under reduced pressure. The
residue obtained is dissolved in 200 cm.sup.3 of ethyl acetate,
extracted once with 100 cm.sup.3 of water, once with 30 cm.sup.3 of
10% aqueous sodium hydroxide solution, and twice with 50 cm.sup.3
of water. The organic phase is dried over anhydrous magnesium
sulfate, filtered, and evaporated under reduced pressure. The
residue is subjected to chromatography over a silica gel column
using a 4:3:5:0.2 mixture of ethyl acetate, hexane, chloroform and
methanol. The fractions containing the active substance are
collected, evaporated, and the residue is dissolved in a 30:1
mixture of diethyl ether and ethyl acetate. To the solution,
diethyl ether containing hydrogen chloride are added, drop by drop,
under stirring at room temperature. The crystals obtained are
filtered and washed with diethyl ether.
Thus, 3.65 g (36.0%) of the title compound are obtained. M.p.:
207-209.degree. C.
Analysis: for C.sub.24 H.sub.28 Cl.sub.2 N.sub.4 O.sub.4 (507.42);
calc.: C, 56.81%; H, 5.56%; Cl, 13.97%; N, 11.04%; found: C,
56.24%; H, 5.51%; Cl, 13.90%,N 10.74%.
IR (KBr): 2931, 1641, 1607.
.sup.1 H-NMR (DMSO-d.sub.6, i400): 12.79 (s, 1H), 11.22 (bs, 1H),
7.66 (m, 2H), 7.59 (m, 3H), 7.40 (m, 3H), 6.76 (.about.t, 1H), 6.72
(.about.t, 1H), 6.60 (dd, 1H), 6.54 (dd, 1H), 4.46 (m, 5H), 4.22
(s, 4H), 3.68 (m, 2H), 3.48 (m, 2H), 3.18 (m, 2H), 2.10 (m,
2H).
.sup.13 C-NMR(CDCl.sub.3, i400): 156.87, 147.11, 144.35, 139.72,
139.44, 133.81, 131.47, 130.07, 129.53, 128.83, 120.13, 110.79,
106.54, 106.37, 64.09, 64.06, 63.79, 56.74, 50.67, 49.58, 40.25,
24.98.
Example 4
Preparation of
5-chloro-4-{4-[4-(2,3-dihydrobenzo[1,4]dioxine-5-yl)-piperazine-1-yl]-buty
lamino}-2H-piridazine-3-one
A mixture of 1.65 g (0.01 moles) of
4,5-dichloro-2H-pyridazine-3-one, 7.28 g (0.025 moles) of
4-(4-(2,3-dihydrobenzo[1,4]-dioxine-5-yl)-piperazine-1-yl)-butylamine
and 40 cm.sup.3 of dioxane is stirred at reflux temperature under
reflux for 24 hours. Then, the reaction mixture is evaporated under
reduced pressure. The residue obtained is dissolved in toluene,
extracted with a 10% aqueous sodium carbonate solution, then
several times with water. The organic phase is dried over anhydrous
magnesium sulfate, filtered, and the filtrate is evaporated under
reduced pressure. The residue obtained is subjected to
chromatography over a silica gel column using a 3:2:0.5 mixture of
hexane, acetone and methanol as the eluent. The fractions
containing the active substance are collected and evaporated. The
residue is rubbed with diethyl ether, the formed crystals are
filtered.
Thus, 1.91 g (45,6%) of the title compound are obtained. M.p.:
160-162.degree. C.
Analysis: for C.sub.20 H.sub.25 ClN.sub.5 O.sub.3 (419.92); calc.:
C, 57.21%; H, 6.24%; Cl, 8.44%; N, 16.68%; found: C, 57.26%; H,
6.32%; Cl, 8.33%; N, 16.49%.
IR(KBr): 3345, 1648, 1613.
.sup.1 H-NMR (CDCl.sub.3, i400): 11.02 (bs, 1H), 7.52 (s, 1H), 6.77
(t, 1H, J=8.1 Hz), 6.59 (dd, 1H, J1=1.4 Hz, J2=8.2 Hz), 6.54 (dd,
1H, J1=1.5 Hz, J2=8.0 Hz), 5.89 (m, 1H), 4.28 (m, 4H), 3.77
(.about.q, 2H, J=6.7 Hz), 3.11 (m, 4H), 2.67 (m, 4H), 2.46 (t, 2H,
J=7.0 Hz), 1.68 (m, 4H).
Example 5
Preparation of
4-chloro-5-{2-[4-(2,3-dihydrobenzo[1,4]dioxine-5-yl)-piperazin-1-yl]-ethyl
amino}-2H-pyridazine-3-one
A mixture of 1.33 g (0.006 moles) of
1-(2,3-dihydro-1,4-benzodioxine-5-yl)-piperazine, 4.5 cm.sup.3 of
dimethylformamide, 2 cm.sup.3 (0.014 moles) of triethylamine, 0.1 g
(0.0006 moles) of potassium iodide es 1.23 g (0,0049 moles) of
5-(2-bromo-ethylamino)-4-chloro-2H-pyridazine-3-one is stirred for
4 hours at room temperature. Then, a solution prepared from 33 cm
of water and 1.2 g (0.014 moles) of sodium hydrogen carbonate is
added. Due to the water, a precipitate is formed. The crystals are
filtered, and washed several times with water. The crude product is
dissolved in acetonitrile under stirring at reflux temperature,
filtered, and the filtrate is evaporated to the fifth of the
original volume. Then, the solution is stirred under cooling with
ice water, and the crystals obtained are filtered.
Thus, 1.51 g (78.6%) of the title compound are obtained. M.p.:
217-219.degree. C.
Analysis: for C.sub.18 H.sub.22 ClN.sub.5 O.sub.3 (391.86); calc.:
C, 55.17%; H, 5.66%; Cl, 9.05%; N, 17.87%; found: C, 54.99%;H
5.68%; Cl, 8.80%,N 18.16%.
IR (KBr): 3360, 1637, 1602.
.sup.1 H-NM (CDCl.sub.3, i400): 11.38 (bs, 1H), 7.63 (s, 1H), 6.78
(t, 1H, J=8.1 Hz), 6.61 (dd, 1H, J1=1.5 Hz, J2=8.2 Hz), 6.55 (dd,
1H, J1=1.5 Hz, J2=8.0 Hz), 5.80 (bs, 1H), 4.29 (m, 4H), 3.43 (m,
2H), 3.12 (m, 4H), 2.74 (m, 6H).
Example 6
Preparation of
4-chloro-5-{2-[4-(2,3-dihydro-1,4-benzodioxine-5-yl)-piperazine-1-yl]-ethy
lamino}-2-methyl-2H-piridazine-3-one monohydrate
A mixture of 1.31 g (0.0059 moles) of
4-chloro-5-(2-chloroethylamino)-2-methyl-2H-pyridazine-3-one, 1.5 g
(0.0068 moles) of 1-(2,3-dihydro-benzo[1,4]dioxine-5-yl)piperazine,
1.68 g (0.012 moles) of potassium carbonate, 0.2 g of potassium
iodide and 34 cm.sup.3 of acetonitrile is stirred at reflux
temperature under reflux for 48 hours. The reaction mixture is
filtered, the filtrate is evaporated under reduced pressure, the
residue obtained is, at first, recrystallized from 2-propanol, then
from acetonitrile.
Thus, 1.25 g (71.1%) of the title compound are obtained. M.p.:
132-134.degree. C.
Analysis: for C.sub.19 H.sub.26 ClN.sub.5 O.sub.3 (492.83); calc.:
C, 53.84%; H, 6.18%; Cl, 8.36%; N, 16.52%; found: C, 54.02%; H,
6.39%; Cl, 8.37%; N, 16.71%.
IR (KBr): 3335, 1633, 1263.
.sup.1 H-NMR (DMSO-d.sub.6, i400): 7.87 (s, 1H), 6.70 (.about.t,
J=8.1 Hz, 1H), 6.49 (dd, J1=1.1 Hz, J2=8.2 Hz, 1H), 6.44 (dd,
J1=1.1 Hz, J2=8.0 Hz, 1H), 6.36 (bt, J=5.8 Hz, 1H), 4.22 (m, 2H),
4.19 (m, 2H), 3.58 (s, 3H), 3.45 (.about.q, J=6.1 Hz, 1H), 2.94 (m,
4H), 2.57 (m, 6H).
.sup.13 C-NMR (DMSO-d.sub.6, i400): 156.89, 144.75, 143.99, 141.71,
136.33, 126.82, 120.47, 111.20, 110.35, 104.68, 63.97, 63.87,
57.17, 53.03, 50.34, 39.62.
Example 7
Preparation of
4-chloro-5-{2-[4-(2,3-dihydrobenzo[1,4]dioxine-5-yl)-piperazine-1-yl]ethyl
}methylamino-2H-pyridazine-3-one
A mixture of 4.65 g (0.021 moles) of
4-chloro-5-[(2-chloroethyl)-methylamino]-2H-piridazine-3-one, 6.6 g
(0.03 moles) of 1-(2,3-dihydrobenzo[1,4]dioxine-5-yl)piperazine,
5.1 cm.sup.3 of triethyl-amine and 12 cm.sup.3 of dimethylformamide
is stirred at reflux temperature under reflux for 48 hours. Then,
water is added to the reaction mixture, the pH is adjusted to 10 by
the addition of aqueous sodium hydroxide solution, and the aqueous
phase is extracted twice with dichloromethane. The combined organic
phases are washed with water several times, dried over anhydrous
magnesium sulfate, filtered, and the filtrate is evaporated under
reduced pressure. The residue is subjected to chromatography over a
silica gel column using a 2:1:0.5 mixture of ethyl acetate, hexane
and methanol as the eluent. The fractions containing the active
substance are collected, evaporated, the residue is suspended in
diethyl ether. The crystals obtained are filtered.
Thus, 2.4 g (28.2%) of the title compound are obtained. M.p.:
214-215.degree. C.
Analysis: for C.sub.19 H.sub.24 ClN.sub.5 O.sub.3 (405.89); calc.:
H, 5.96%; Cl, 8.73%; N, 17.25%; found: H, 5.68%; Cl, 8.94%; N,
16.89%.
IR (KBr): 2827, 1641, 1596.
.sup.1 H-NMR (DMSO-d.sub.6, g200): 12.71 (bs, 1H), 7.86 (s, 1H),
6.70 (.about.t, J=8.1 Hz, 1H), 6.48 (dd, J1=1.5 Hz, J2=8.3 Hz, 1H),
6.38 (dd, J1=1.5 Hz, J2=8.3 Hz, 1H), 4.20 (.about.s, 4H), 3.59 (t,
J=6.1 hz, 2H), 3.06 (s, 3H), 2.81 (m, 4H), 2.56 (t, J=6.3 Hz, 2H),
2.48 (m, 4H).
.sup.13 C-NMR (DMSO-d.sub.6, g200):158.91, 148.77, 144.00, 141.68,
136.31, 132.43, 120.47, 111.21, 110.90, 110.26, 63.97, 55.09,
53.06, 50.29, 40.95, 40.53.
Example 8
Preparation of 2-tert.
-butyl-5-chloro-4-{2-[4-(2,3-dihydrobenzo-[1,4]dioxine-5-yl)piperazine-1-y
l]ethylamino}-2H-pyridazine-3-one
A mixture of 2.71 g (0.00122 moles) of
2-tert-butyl-4,5-dichloro-2H-pyridazine-3-one, 4.67 g (0.0177
moles) of
2-[4-(2,3-dihydrobenzo[1,4]-dioxine-5-yl)piperazine-1-yl]ethylamin,
60 cm.sup.3 of dioxane and 3.3 g of potassium carbonate is stirred
at reflux temperature under reflux for 24 hours. Then, the reaction
mixture is filtered, the filtrate is evaporated under reduced
pressure, the residue is subjected to chromatography over a silica
gel column using a 2:1 mixture of hexane and acetone as the eluent.
The fractions containing the active substance are collected,
evaporated, the residue is suspended in diisopropyl ether, and the
crystals obtained are filtered.
Thus, 1.34 g (24.5%) of the title compound are obtained. M.p.:
177-178.degree. C.
Analysis: for C.sub.22 H.sub.30 ClN.sub.5 O.sub.3 (447.97); calc.:
C, 58.99%; H, 6.75%; Cl, 7.91%; N, 15.63%; found: C, 58.78%; H,
6.66%; Cl, 7.80%; N, 15.35%.
IR (KBr): 3321, 1602, 1475, 1143, 998.
.sup.1 H-NMR (CDCl.sub.3, i400): 7.45 (s, 1H), 6.77 (.about.t,
J=8.1 Hz, 1H), 6.59 (d, J=8 Hz, 1H), 6.54 (d, J=8.0 Hz, 1H), 6.35
(bt, 1H), 4.31 (m, 2H), 4.24 (nm, 2H), 3.87 (.about.q, J=5.6 Hz,
2H), 3.13 (m, 4H), 2.71 (m, 6H), 1.62 (s, 9H).
.sup.13 C-NMR(CDCl.sub.3, i400): 156.44, 144.02, 141.58, 140.32,
137.37, 136.38, 120.60, 111.90, 110.74, 106.2, 64.73, 64.29, 63.91,
57.57, 53.01, 50.48, 40.53, 27.84.
Example 9
Preparation of
4-{3-[2-(2,3-dihydrobenzo[1,4]dioxine-5-yloxy)ethylamino]-propylamino}-2H-
pyridazine-3-one
12.52 g (0.027 moles) of
4-(3-{benzyl-[2-(2,3-dihydrobenzo-[1,4]dioxine-5-yloxy)ethylamino]propylam
ino}-5-chloro-2H-pyridazine-3-one, 420 cm.sup.3 of methanol, 1.2 g
(0.03 moles) of sodium hydroxide and 12.5 g of palladium on carbon
catalyst consisting of 8% of Pd, 28% of C and 64% of H.sub.2 O are
transferred into an autoclave. The reaction mixture is stirred at
room temperature and under a hydrogen pressure of 10 atm for 48
hours. Then, the excess hydrogen is let out from the autoclave, the
reaction mixture is filtered, and the catalyst is washed three
times using 100 cm.sup.3 of water each time. The filtrate is
evaporated under reduced pressure, and the residue is subjected to
chromatography over a silica gel column using a 4:1 mixture of
dichloromethane and methanol as the eluent. The fractions
containing the active substance are combined, evaporated, the
residue is suspended in diisopropyl ether. The crystals obtained
are filtered.
Thus, 5.92 g (63.4%) of the title compound are obtained. M.p.:
118-120.degree. C.
IR (KBr): 3289, 1646, 16136, 1112.
.sup.1 H-NMR (DMSO-d.sub.6, i400): 12.50 (b, 1H), 7.55 (d, J=4.9
Hz, 1H), 6.79 (bt, J=5.9 Hz, 1H), 6.74 (.about.t, J=8.2 Hz, 1H),
6.60 (dd, J1=1.4 Hz, J2=8.2 Hz, 1H), 6.53 (dd, J1=1.5 Hz, J2=8.2
Hz, 1H), 6.09 (d, J=4.9 Hz, 1H), 4.22 (s, 4H), 4.18 (t, J=5.4 Hz,
2H), 3.21 (.about.q, J=6.3 Hz, 2H), 3.16 (t, J=5.4 Hz, 2H), 2.92
(t, J=7.3 Hz, 2H), 1.87 (.about.qn, J=7.1 Hz, 2H).
Hydrochloride of the title compound
M.p.: 203-204.degree. C.
Analysis: for C.sub.17 H.sub.23 ClN.sub.4 O.sub.4 (382.85); calc.:
C, 53.23%; H, 6.06%; Cl, 9.26%; N, 14.63%; found: C, 53.26%; H,
6.05%; Cl, 9.14%; N, 19.41%.
.sup.1 H-NMR (DMSO-d.sub.6, i400): 12.50 (b, 1H), 7.55 (d, J=4.9
Hz, 1H), 6.79 (bt, J=5.9 Hz, 1H), 6.74 (.about.t, J=8.2 Hz, 1H),
6.60 (dd, J1=1.4 Hz, J2=8.2 Hz, 1H), 6.53 (dd, J1=1.5 Hz, J2=8.2
Hz, 1H), 6.09 (d, J=4.9 Hz, 1H), 4.22 (s, 4H), 4.18 (t, J=5.4 Hz,
2H), 3.21 (.about.q, J=6.3 Hz, 2H), 3.16 (t, J=5.4 Hz, 2H), 2.92
(t, J=7.3 Hz, 2H), 1.87 (.about.qn, J=7.1 Hz, 2H).
Example 10
Preparation of
5-{2-[4-(2,3-dihydro-1,4-benzodioxine-5-yl)-piperazine-1-yl]-ethylamino}-2
H-pyridazine-3-one
3.9 g (0.01 moles) of
4-chloro-5-{2-[4-(2,3-dihydro-1,4-benzodioxine-5-yl)piperazine-1-yl]ethyla
mino}-2H-pyridazine-3-one, 400 cm.sup.3 of a 9:1 mixture of
methanol and distilled water, 0.45 g (0.0112 moles) of sodium
hydroxide and 4 g of palladium catalyst consisting of 8% of Pd, 28%
of C and 64% of H.sub.2 O are weighed into an autoclave. The
reaction mixture is stirred at room temperature and under a
hydrogen pressure of 10 atm for 3 hours. Then, the excess hydrogen
is let out from the autoclave, the reaction mixture is heated to
reflux temperature and stirred at this temperature for 5 minutes,
then filtered while hot, and the catalyst is washed three times
using 33 cm.sup.3 of a 1:1 mixture of methanol and dichloromethane
each time. The combined filtrates are evaporated to a volume of 30
cm.sup.3, the solution obtained is stirred for half an hour under
cooling with ice water, the crystals obtained are filtered and
washed with 10 cm.sup.3 of cooled methanol. The product is dried at
140.degree. C. over phosphorus pentoxide in vacuo for 3 hours.
Thus, 2.92 g (81.7%) of the title compound are obtained. M.p.:
244-246.degree. C.
Analysis: for C.sub.18 H.sub.23 N.sub.5 O.sub.3 (357.42); calc.: C,
60.49%; H, 6.49%; N, 19.59%; found: C, 60.33%; H, 6.44%; N,
19.46%.
IR (KBr): 3325, 3277, 1612.
.sup.1 H-NMR (CDCl.sub.3, i400): 11.85 (bs, 1H), 7.44 (d, J=2.1 Hz,
1H), 6.80 (bt, 1H), 6.66 (.about.t, J=8.1 Hz, 1H), 6.44 (d, J=8.2
Hz, 1H), 6.41 (d, J=8.1 Hz, 1H), 5.35 (.about.s, 1H), 4.16 (m, 2H),
3.08 (.about.q, J=5.4 Hz, 2H), 2.92 (m, 4H), 2.51 (m, 6H).
.sup.13 C-NMR(CDCl.sub.3, i400): 162.31, 149.38, 143.99, 141.75,
136.34, 131.65, 120.48, 111.19, 110.33, 94.32, 63.98, 63.88, 55.91,
53.13, 50.16, 39.15.
Hydrochloride of the title compound
IR (KBr): 3250, 2591, 1085.
.sup.1 H-NMR (DMSO-d.sub.6, i400): 12.04 (bs, 1H), 11.33 (bs, 1H),
7.49 (m, 1H), 6.76 (t, J=8.1 Hz, 1H), 6.58 (dd, J1=1.2 Hz, J2=8.2
Hz, 1H), 6.52 (dd, J1=1.1 Hz, J2=7.9 Hz, 1H), 5.62 (d, J=2.3 Hz,
1H), 4.25 (m, 2H), 4.23 (m, 2H), 3.7-3.0 (m, 12H).
.sup.13 C-NMR (DMSO-d.sub.6, i400): 162.31, 148.86, 144.15, 140.02,
136.30, 131.55, 120.65, 112.14, 110.59, 95.44, 64.12, 63.92, 53.29,
51.42, 47.06, 36.19.
Example 11
Preparation of
5-{2-[4-(7-chloro-2,3-dihydrobenzo[1,4]dioxine-5-yl)-piperazine-1-yl]ethyl
amino}-2H-pyridazine-3-one
A mixture of 3.24 g (0.0127 moles) of
1-(7-chloro-2,3-dihydro-benzo-[1,4]dioxine-5-yl)piperazine, 5
cm.sup.3 of dimethylformamide, 3.6 cm.sup.3 of triethylamine and
1.82 g (0.0086 moles) of 5-(2-chloroethylamino)-2H-pyridazine-3-one
hydrochloride is stirred at reflux temperature for 2 hours. To the
reaction mixture, a solution of 3.17 g of sodium hydrogen carbonate
in 50 cm.sup.3 of water is added, drop by drop. Due to the presence
of the water, oil separates. The water is decanted from the oil,
and 30 cm.sup.3 of dichloro-methane are added to the residue. The
crystals separating under stirring are filtered.
Thus, 1.35 g (27.2%) of the title compound are obtained. M.p.:
115-117.degree. C.
Analysis: for C.sub.18 H.sub.22 ClN.sub.5 O.sub.3 (391.86); calc.:
H, 5.66%; Cl, 9.05%; N, 17.87%; found: H, 5.68%; Cl, 9.14%; N,
17.23%.
IR (KBr): 3266, 1616, 1066, 1005.
.sup.1 H-NMR (DMSO-d.sub.6, i400): 11.89 (bs, 1H), 7.50 (d, J=2.4
Hz, 1H), 6.90 (b, 1H), 6,58 (d, J=2.4 Hz, 1H), 6.45 (d, J=2.4 Hz,
1H), 5.40 (d, J=1.70 Hz, 1H), 4.24 (.about.s, 4H), 3.14 (q, J=5.1
Hz, 2H), 3.00 (m, 4H), 2.57 (m, 6H).
.sup.13 C-NMR (DMSO-d.sub.6, i400): 162.32, 149.38, 144.45, 142.61,
135.14, 131.66, 124.32, 110.69, 110.44, 94.33, 64.12, 63.96, 55.80,
52.92, 49.82, 39.08.
Example 12
Preparation of
5-{3-[4-(2,3-dihydro-1,4-benzodioxine-5-yl)piperazine-1-yl]-propylamino}-2
H-pyridazine-3-one
2.94 g (0.007 moles) of
4-chloro-5-{3-[4-(2,3-dihydro-1,4-benzodioxine-5-yl)-piperazine-1-yl]propy
lamino}-2H-pyridazine-3-one, 300 cm.sup.3 of a 9:1 mixture of
methanol and water and 3 g of palladium on carbon catalyst
consisting of 8% of Pd, 28% of C and 64% of H.sub.2 O are weighed
into an apparatus of 1000 cm.sup.3 volume equipped with a reflux
condenser connected to a bubbling device. 1.5 cm.sup.3 of hydrazine
hydrate are added, drop by drop, to the reaction mixture that is
then stirred at reflux temperature for 2 hours. The mixture is
filtered, and the catalyst is washed three times using 33 cm.sup.3
of a 1:1 mixture of methanol and dichloromethane. The combined
filtrates are evaporated, and the residue is dissolved in 90
cm.sup.3 of a 1:1 mixture of 2-propanol and water under heating,
the solution is filtered, and the filtrate is evaporated to the
half of the original volume. After cooling, the crystals separated
are stirred for flirter half an hour under cooling with ice water,
then filtered and washed with diethyl ether. The product is dried
at 60.degree. C. over phosphorus pentoxide in vacuo for 3
hours.
Thus, 2.16 g (83.1%) of the title compound are obtained. M.p.:
158-160.degree. C.
Analysis: for C.sub.19 H.sub.25 N.sub.5 O.sub.3 (371.44); calc.: C,
61.44%; H, 6.78%; N, 18.85%; found: C, 60.98%; H, 6.75%; N,
18.61%.
IR (KBr): 3315, 1614, 1275, 1105.
.sup.1 H-NMR (DMSO-d.sub.6, i400): 11.89 (bs, 1H), 7.42 (d, J=2.4
Hz, 1H), 6.99 (bt, J=5.2 Hz, 1H), 6.71 (.about.t, J=8.1 Hz, 1H),
6.49 (dd, J1=1.3 Hz, J2=8.2 Hz, 1H), 6.46 (dd, J1=1.3 Hz, J2=8.1
Hz, 1H), 5.37 (d, J=2.2 Hz, 1H), 4.23 (m, 2H), 4.20 (m, 2H), 3.03
(.about.q, J=5.7 Hz, 2H), 2.97 (m, 4H), 2.51 (m, 4H), 2.40 (t,
J=6.8 Hz, 2H), 1.70 (qn, J=6.8 Hz, 2H).
.sup.13 C-NMR (CDCl.sub.3, i400): 162.32, 149.46, 143.99, 141.77,
136.33, 131.57, 120.47, 111.17, 110.34, 94.07, 63.98, 63.88, 55.43,
53.14, 50.25, 39.07.
Example 13
Preparation of
5-{2-[2-(2,3-dihydrobenzo[1,4]dioxine-5-yloxy)ethylamino)-ethylamino)-2H-p
yridazine-3-one
3.4 g (0.0075 moles) of
5-{2-[benzyl-[2-(2,3-dihydrobenzo-[1,4]dioxine-5-yloxy)ethyl]amino]ethylam
ino}-4-chloro-2H-pyridazine-3-one, 170 cm.sup.3 of a mixture of
ethanol and 70 cm.sup.3 of water, and 3.4 g of palladium on carbon
catalyst consisting of 8% of Pd, 28% of C and 64% of H.sub.2 O are
weighed into an apparatus of 500 cm.sup.3 volume equipped with a
reflux condenser connected to a bubbling device. 6.8 cm.sup.3 of
hydrazine hydrate are added, drop by drop, to the reaction mixture
that is then stirred at room temperature for 1 hour, and at reflux
temperature. for 2 hours. The mixture is filtered, and the catalyst
is washed three times using 33 cm.sup.3 of a 1:1 mixture of
methanol and dichloromethane. The combined filtrates are evaporated
to a volume of 20 cm.sup.2, the residue is cooled, the crystals
formed are stirred under cooling with water for further half an
hour, then filtered and washed with diethyl ether. The crude
product obtained is recryystalized from acetonitie.
Thus, 2.26 g (83.1%) of the title compound are obtained. M.p.:
81-83.degree. C.
Analysis: for: C.sub.16 H.sub.20 N.sub.4 O.sub.4 (332.36); calc.:
C, 57.82%; H, 6.07%; N, 16.86%; found: C, 57.70%; H, 6.08%; N,
16.78%.
IR (KBr): 3248, 3060, 1616, 1110.
.sup.1 H-NMR (DMSO-d.sub.6, i400): 11.91 (bs, 1H), 7.46 (d, J=2.5
Hz, 1H), 6.93 (bt, J=5.3 Hz, 1H), 6.71 (.about.t, J=8.2 Hz, 1H),
6.55 (dd, J1=1.4 Hz, J2=8.2 Hz, 1H), 6.47 (dd, J1=1.4 Hz, J2=8.2
Hz, 1H), 5.41 (d, J=2.6 Hz, 1H), 4.21 (s, 4H), 3.99 (t, J=5.7 Hz,
2H), 3.09 (.about.q, J=5.9 Hz, 2H), 2.89 (t, J=5.6 Hz, 2H), 2.77
(t, J=6.2 Hz, 2H), 1.97 (b, 1H).
.sup.13 C-NMR (DMSO-d.sub.6, i400): 162.39, 149.54, 148.25, 144.23,
133.72, 131.69, 120.06, 109.97, 106.21, 94.20, 68.82, 64.04, 63.92,
48.21, 47.36, 41.95.
Example 14
Preparation of
5-{2-[4-(2,3-dihydro1,4-benzodioxine-5-yl)-piperazine-1-yl]-ethylamino}-2-
methyl-2H-pyridazine-3-one
A mixture of 3.19 g (0.0145 moles) of
1-(2,3-dihydrobenzo-[1,4]dioxin-5-yl)-piperazine, 80 cm.sup.3 of
acetonitrile, 5.32 g (0.038 moles) of potassium carbonate, 0.3 g
potassium iodide and 2.88 g (0.0129 moles) of
5-(2-chloro-ethylamino)-2-methyl-2H-pyridazine-3-one hydrochloride
is stirred at reflux temperature for 48 hours. Then the reaction
mixture is cooled to room temperature, and filtered. The filtered
matter is dissolved in 100 cm.sup.3 of water and 100 cm.sup.3 of
dichloromethane, the organic phase is separated, the aqueous phase
is extracted three times using 50 cm.sup.3 of dichloromethane each
time. The combined organic phases are washed with 25 cm.sup.3 of
water saturated with sodium chloride, dried over anhydrous
magnesium sulfate, and evaporated under reduced pressure. The
residue is recrystallized from acetonitrile.
Thus, 2.8 g (58.6%) of the title compound are obtained. M.p.:
188-190.degree. C.
Analysis: for C.sub.19 H.sub.25 N.sub.5 O.sub.3 (371.44); calc.: C,
61.44%; H, 6.78%; N, 18.85%; found: C, 61.49%; H, 6.76%; N,
18.76%.
IR (KBr): 3281, 1614, 1277.
.sup.1 H-N (DMSO-d.sub.6, i400): 7.52 (d, J=2.7 Hz, 1H), 6.80 (bt,
1H, 6.71 (.about.t, J=8.1 Hz, 1H), 6.47 (m, 2H), 5.49 (d, J=2.7 Hz,
1H), 4.22 (m, 2H), 4.20 (m, 2H), 3.46 (s, 3H), 3.13 (.about.q,
J=5.6 Hz, 2H), 2.97 (m, 4H), 2.55 (m, 6H).
.sup.13 C-NMR (DMSO-d.sub.6, i400): 161.03, 149.14, 143.99, 141.76,
136.33, 130.98, 120.47, 111.18, 110.32, 94.37, 63.97, 63.87, 55.94,
53.13, 50.18, 39.28, 38.30.
Example 15
Preparation of
5-({2-[4-(2,3-dihydro-benzo[1,4]dioxine-5-yl)-piperazine-1-yl]-ethyl}-meth
yl-amino)-2H-pyridazine-3-one-hydrochloride-monohydrate
Into a pressure-proof hydrogenating apparatus 0.8 g (0.002 mole) of
4-chloro-5-({2-[4-(2,3-dihydro-benzo[1,4]dioxine-5-yl)-piperazine-1-yl]-et
hyl}-methyl-amino)-2H-pyridazine-3-one, 20 cm.sup.3 of methanol and
0.8 g of a palladium charcoal catalyst (8% Pd, 28% C, 64% H.sub.2
O) are introduced. The reaction mixture is stirred at room
temperature under a hydrogen pressure of 10 atm. for 2 hours. The
hydrogen is released, the reaction mixture is filtered and the
filtrate is evaporated. To the residue 10 cm.sup.3 of toluene are
added and the mixture is distilled off in vacuo. The residue is
suspended in 10 ml of diisopropyl ether. The crystals are filtered.
The crude product is recrystallized from a 9:1 mixture of
acetonitrile and water.
Thus, 0.62 g (73.8%) of the desired product are obtained. M.p.:
234-236.degree. C.
Analysis: for C.sub.19 H.sub.28 ClN.sub.5 O.sub.4 (425.92); calc.:
C, 53.58%; H, 6.63%; Cl, 8.32%; N, 16.44%; found: C, 53.06%; H,
6.39%; Cl, 8.20%; N, 16.23%.
IR (KBr): 3389, 2414, 1653, 1600, 1473.
.sup.1 H-NMR (DMSO-d.sub.6, i400): 12.23 (bs, 1H), 11.41 (b, 1H),
7.91 (d, J=2.7 Hz, 1H), 6.76 (.about.t, J=8.1 Hz, 1H), 6.58 (dd,
J1=1.2 Hz, J2=8.2 Hz, 1H), 6.52 (dd, J1=1.2 Hz, J2=8.1 Hz, 1H),
6.64 (.about.s, 1H), 4.25 (m, 2H), 4.23 (m, 2H), 3.89 (m, 2H), 3.52
(m, 4H), 3.4-3.0 (m, 6H), 2.98 (s, 3H).
.sup.13 C-NMR (DMSO-d.sub.6, i400): 161.82, 149.04, 144.14, 139.98,
136.28, 128.75, 120.62, 112.11, 110.60, 98.22, 64.10, 63.90, 51.47,
51.16. 47.09, 45.21, 37.61.
Example 16
Preparation of
5-(2-(4-(2,3-dihydro-benzo[1,4]dioxine-5-yl)-piperazine-1-yl)-ethyl-methyl
-amino)-2-methyl-2H-pyridazine-3-one-hydrochloride
Into a pressure-proof hydrogenating apparatus 4.0 g (0.0095 mole)
of
4-chloro-5-({2-[4-(2,3-dihydro-benzo[1,4]dioxine-5-yl)-piperazine-1-yl]-et
hyl}-methyl-amino)-2-methyl-2H-pyridazine-3-one, 300 cm.sup.3 of
methanol and 4.0 g of a palladium charcoal catalyst (8% Pd, 28% C,
64% H.sub.2 O) are weighed in. The reaction mixture is stirred at
room temperature under a hydrogen pressure of 10 atm. for 3 hours.
The hydrogen is released, the reaction mixture is filtered and the
catalyst is washed 4 times with 50 cm.sup.3 of methanol each and
the mother lye is evaporated. To the residue 30 ml of toluene are
added and the solvent is distilled off in vacuo. The residue is
suspended in diisopropyl ether, the precipitated crystals are
filtered, the crude product is dissolved in a 9:1 mixture of
acetonitrile and water under reflux, filtered and the filtrate is
evaporated to half volume. The residual mother lye is cooled and
stirred. The precipitated crystals are filtered.
Thus, 3.02 g (75.5%) of the desired product are obtained. M.p.:
249-251.degree. C.
Analysis: for C.sub.20 H.sub.28 ClN.sub.5 O.sub.3 (421.93); calc.:
C, 56.93%; H, 6.69%; Cl, 8.40%; N, 16.60%; found: C, 56.55%; H,
6.39%; Cl, 8.72%; N, 16.8%.
IR (KBr): 2345, 1637, 1596, 1477, 1088.
.sup.1 H-NMR (DMSO-d.sub.6, g200): 11.25 (b, 1H), 7.94 (d, J=2.7 Hz
1H), 6.77 (.about.t, J=8.1 Hz, 1H), 6.55 (m, 2H), 5.76 (d, J=2.7
Hz, 1H), 4.24 (s, 4H), 3.88 (m, 2H), 3.7-2.9 (m, 10H), 3.53 (s,
3H), 2.98 (s, 3H).
.sup.13 C-NMR (DMSO-d.sub.6, i400): 160.46, 148.76, 144.10, 139.89,
136.25, 128.15, 120.53, 112.02, 110.55, 98.13, 64.04, 63.84, 51.48,
47.03. 45.17, 37.52.
Example 17
Preparation of
4-chloro-5-({2-[4-(2,3-dihydro-benzo[1,4]dioxine-5-yl)-piperazine-1-yl]-et
hyl}-methyl-amino)-2-methyl-2H-pyridazine-3-one
7.48 g (0.034 mole) of
1-(2,3-dihydro-benzo[1,4]dioxine-5-yl)-piperazine, 7.1 g (0.066
mole) of sodium carbonate, 1.13 g (0.0075 mole) of sodium iodide,
7.23 g (0.031 mole) of
5-(2-chloro-ethylamino)-4-chloro-2-methyl-2H-pyridazine-3-one and
42 cm.sup.3 of dimethyl formamide are admixed. The reaction mixture
is stirred at 110.degree. C. at 4 hours, whereupon 270 cm.sup.3 of
water are added dropwise and the aqueous phase is extracted 3 times
in 100 ml of ethyl-acetate each. The united organic phases are
washed twice with 100 ml of water and twice with 50 ml of a
saturated aqueous sodium chloride solution each, dried over
magnesium sulfate and filtered. The organic phase is evaporated and
the residue is suspended in a mixture of ethyl acetate and
n-hexane. The crystals are filtered and dried. The crude product is
recrystallized from 2-propanol.
Thus, 7.67 g (59.0%) of the desired compound are obtained. M.p.:
114-116.degree. C.
Analysis: for C.sub.20 H.sub.26 ClN.sub.5 O.sub.3 (419.91); calc.:
C, 57.21%; H, 6.24%; Cl, 8.44%; N, 16.68%; found: C, 57.05%; H,
6.21%; Cl, 8.33%; N, 16.47%.
IR (Kr): 1642, 1591, 1473, 998.
.sup.1 H-NMR (DMSO-d.sub.6, i400): 7.88 (s, 1H), 6.70, (.about.t,
J=8.1 Hz, 1H), 6.48 (dd, J1=1.4 Hz, J2=8.2 Hz, 1H), 6.39 (dd,
J1=1.4 Hz, J2=8.0 Hz, 1H), 4.21 (m, 2H), 4.20 (m, 2H), 3.59 (s,
3H), 3.59 (t, 2H), 3.06 (s, 3H), 2.82 (m, 4H), 2.56 (t, J=6.3 Hz,
2H), 2.50 (m).
.sup.13 C-NMR (DMSO-d.sub.6, i400): 157.74, 148.29, 143.98, 141.68,
136.31, 131.45, 120.45, 111.19, 111.01, 110.21, 63.95, 63.85,
55.15, 53.05, 50.28. 50.03, 39.81 39.7.
Example 18
Preparation of
5-(2-{benzyl-[2-(2,3-dihydro-benzo[1,4]dioxine-5-yl-oxy)-ethyl]-amino}-eth
yl-amino)-4-chloro-2-methyl-2H-pyridazine-3-one
A mixture of 4.95 g (0.017 mole) of
benzyl-[2-(2,3-dihydro-benzo[1,4]dioxine-5-yl-oxy)-ethyl]-amine,
4.68 g (0.044 mole) of sodium carbonate, 0.73 g (0.0047 mole) of
sodium iodide, 4.68 g (0.021 mole) of
5-(2-chloro-ethyl-amino)-4-chloro-2-methyl-2H-pyridazine-3-one and
26 cm.sup.3 of dimethyl formamide are stirred at 110.degree. C. for
5 hours. To the reaction mixture 200 cm.sup.3 of water are added
dropwise and the aqueous phase is extracted 4 times with 100
cm.sup.3 of dichloro methane each. The united organic phases are
washed successively twice with 100 cm.sup.3 of water each and twice
with 50 cm.sup.3 of a saturated sodium chloride solution each,
dried over magnesium sulfate and filtered. The organic phase is
evaporated. The residue is purified by chromatography on a silica
gel column and elution with a 79:1 mixture of chloroform and
methanol.
Thus, 2.76 g (34.5%) of the desired compound are obtained. M.p:
78-80.degree. C.
IR(KBr): 3381, 3364, 1613, 1113.
.sup.1 H-NMR (DMSO-d.sub.6, i400): 7.39 (s, 1H), 7.33 (m, 2H), 7.28
(m, 2H), 7.23 (m, 1H), 6.73 (.about.t, J=8.3 Hz, 1H), 6.53 (dd,
J1=1.4 Hz, J2=8.3 Hz, 1H), 6.42 (dd, J1=1.3 Hz, J2=8.2 Hz, 1H), 5.
55 (bt, 1H), 4.23 (m, 4H), 4.09 (t, J=5.5 Hz, 2H), 3.75 (s, 2H),
3.72 (s, 3H), 3.32 (.about.q, J=5.6 Hz, 2H), 3.02 (t, J=5.5 Hz,
2H), 2.88 (t, J=5.8 Hz, 2H).
.sup.13 C-NMR (DMSO-d.sub.6, i400): 157.80, 148.00, 144.37, 143.98,
138.55, 133.55, 128.80, 128.49, 127.36, 125.47, 120.15, 10.40,
107.29, 105.32, 67.44, 64.36, 64.13, 59.65, 52.79, 52.64, 40.21,
40.08.
Example 19
Preparation of
5-{2-[2-(2,3-dihydro-benzo[1,4]dioxine-5-yl-oxy)-ethyl-amino]-ethyl-amino}
-2-methyl-2H-pyridazine-3-one-hydrochloride
Into a hydrogenating apparatus 1.75 g (0.0037 mole) of
5-(2-{benzyl-[2-(2,3-dihydro-benzo[1,4]dioxine-5-yl-oxy)-ethyl]-amino}-eth
yl-amino)-4-chloro-2-methyl-2H-pyridazine-3-one, 50 cm.sup.3 of
ethanol, 5 cm.sup.3 of water and 3.5 g of a palladium charcoal
catalyst (8% Pd, 28% C, 64% H.sub.2 O) are introduced. To the
reaction mixture at room temperature 6 cm.sup.3 of hydrazine
hydrate are added dropwise and the temperature is raised to the
boiling point. The reaction mixture is refluxed for half an hour,
filtered off, the catalyst is washed 3 times with 30 cm.sup.3 of
ethanol each and the mother lye is evaporated. To the residue twice
30 ml of toluene each are added and the mixture is evaporated in
vacuo. From the residue salt is formed by using isopropanol
containing hydrogen chloride.
Thus, 1.2 g (84.7%) of the desired compound are obtained. M.p.:
218-219.degree. C.
IR (KBr): 3239, 2512, 1632, 1286, 1100.
.sup.1 H-NMR (DMSO-d.sub.6, i400): 7.55 (d, J=2.8 Hz, 1H), 7.31
(bt, J=5.6 Hz, 1H), 6.81 (.about.t, J=8.2 Hz, 1H), 6.68 (dd, J1=1.5
Hz, J2=8.2 Hz, 1H), 6.58 (dd, J1=1.5 Hz, J2=8.2 Hz, 1H), 5.72 (d,
J=2.7 Hz, 1H), 4.28 (m, 6H), 3.54 (s, 3H), 3.43 (.about.q, J=6.0
Hz, 2H), 3.34 (t, J=5.3 Hz, 2H), 3.16 (t, J=5.3 Hz, 2H).
.sup.13 C-NMR (DMSO-d.sub.6, i400): 160.97, 148.77, 147.44, 144.34,
133.98, 130.85, 120.05, 110.70, 107.09, 95.07, 65.84, 64.00, 46.51,
45.65, 39.7, 38.26.
* * * * *